U.S. patent application number 10/842055 was filed with the patent office on 2004-12-30 for methods for treating depression and other cns disorders using enantiomerically enriched desmethyl-and didesmethyl-metabolites of citalopram.
This patent application is currently assigned to Sepracor Inc.. Invention is credited to Bush, Larry R., Currie, Mark G., Fang, Q. Kevin, Senanayake, Chris H..
Application Number | 20040266864 10/842055 |
Document ID | / |
Family ID | 23321236 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040266864 |
Kind Code |
A1 |
Bush, Larry R. ; et
al. |
December 30, 2004 |
Methods for treating depression and other CNS disorders using
enantiomerically enriched desmethyl-and didesmethyl-metabolites of
citalopram
Abstract
This invention relates to novel compositions of matter
containing enantiomerically enriched (-)-desmethylcitalopram,
(+)-didesmethylcitalopram, or (-)-didesmethylcitalopram or mixtures
thereof in optimal ratios. Contrary to prior teachings, the
enantiomerically enriched citalopram metabolites disclosed herein
possess potent serotonin reuptake inhibitory activity, with minimal
inhibitory effects on the reuptake of other known monoamines, e.g.,
norepinephrine (NE) or dopamine (DA). The present invention also
discloses methods for treating disorders, dysfunctions and diseases
for which inhibition of serotonin reuptake is therapeutically
beneficial. In particular, the present invention discloses a method
for treating various forms of depression with pharmaceutical
compositions described herein.
Inventors: |
Bush, Larry R.; (Worcester,
MA) ; Currie, Mark G.; (Sterling, MA) ; Fang,
Q. Kevin; (Wellesley, MA) ; Senanayake, Chris H.;
(Brookfield, CT) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
Sepracor Inc.
Marlborough
MA
|
Family ID: |
23321236 |
Appl. No.: |
10/842055 |
Filed: |
May 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10842055 |
May 7, 2004 |
|
|
|
PCT/US02/35408 |
Nov 5, 2002 |
|
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60337608 |
Nov 8, 2001 |
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Current U.S.
Class: |
514/469 ;
549/467 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 21/02 20180101; A61P 9/10 20180101; C07D 307/87 20130101; A61P
3/04 20180101; C07D 317/20 20130101; A61P 25/20 20180101; A61P
25/26 20180101; A61P 15/10 20180101; A61P 25/24 20180101; A61P
15/00 20180101; A61P 25/22 20180101; A61P 9/04 20180101; A61P 25/28
20180101; A61P 25/34 20180101; A61P 7/02 20180101; A61P 25/30
20180101; A61P 25/08 20180101; A61P 9/14 20180101; A61P 25/18
20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/469 ;
549/467 |
International
Class: |
C07D 307/78; A61K
031/343 |
Claims
1. A compound having a structure depicted in Formula I, 16wherein
the compound is a racemic, enantiomerically enriched, or optically
pure form of the compound.
2. A compound having a structure depicted in Formula II, 17wherein
the compound is a racemic, enantiomerically enriched, or optically
pure form of the compound.
3. A method for synthesizing (-)-desmethylcitalopram, comprising:
a. reacting 5-cyanophthalide with 4-fluorophenyl magnesium bromide
in the presence of a chiral ligand, followed by reaction with a
second Grignard reagent prepared by reacting 2-bromoethyldioxolane
with magnesium, to afford the (-)-tertiary alcohol shown in Formula
III; 18b. reacting the (-)-tertiary alcohol shown in Formula III
with mesyl chloride followed by acidic treatment to afford the
(-)-aldehyde shown in Formula IV; and 19c. reducing the structure
in Formula IV with sodium borohydride in the presence of
methylamine.
4. The method of claim 3, wherein the resultant amine is isolated
as is or is subsequently reacted with an acid to form a salt.
5. The method of claim 4, wherein the acid used is D-tartaric acid,
L-tartaric acid, HCl or HBr.
6. The method of claim 3, wherein column chromatography with chiral
solid support is used to separate the enantiomers of final or
intermediate products.
7. The method of claim 3, wherein the enantiomeric enrichment
achieved is greater than 80%.
8. The method of claim 3, wherein the enantiomeric enrichment
achieved is greater than 90%.
9. The method of claim 3, wherein the enantiomeric enrichment
achieved is greater than 95%.
10. The method of claim 3, wherein the enantiomeric enrichment
achieved is greater than 99%.
11. A method of synthesizing (-)-didesmethylcitalopram or
(+)-didesmethylcitalopram, said method comprising: 20a. reacting
either the (-)-aldehyde or (+)-aldehyde shown in Formula V with
either (+)-tert-butylsulfinamide or (-)-tert-butylsulfinamide in
the presence of Ti(OEt).sub.4 to give sulfinimine shown in Formula
VI 21 wherein the compound is optically pure or enantiomerically
enriched at each stereocenter designated with asterisks in Formula
VI; and b. reducing the sulfinimine in Formula VI to an amine with
sodium borohydride.
12. The method of claim 11, wherein the resultant amine is isolated
as is or is subsequently reacted with an acid to form a salt.
13. The method of claim 12, wherein the acid used is D-tartaric
acid, L-tartaric acid, HCl or HBr.
14. The method of claim 11, wherein column chromatography with
chiral solid support is used to separate the enantiomers of final
or intermediate products.
15. The method of claim 11, wherein the enantiomeric enrichment
achieved is greater than 80%.
16. The method of claim 11, wherein the enantiomeric enrichment
achieved is greater than 90%.
17. The method of claim 11, wherein the enantiomeric enrichment
achieved is greater than 95%.
18. The method of claim 11, wherein the enantiomeric enrichment
achieved is greater than 99%.
19. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and enantiomerically pure
(-)-desmethylcitalopram, or enantiomerically enriched
(-)-didesmethylcitalopram or (+)-didesmethylcitalopram, or any
combination thereof, or a pharmaceutically acceptable salt, solvate
or clathrate thereof.
20. A method of treating one or more disorders, dysfunctions or
diseases for which serotonin reuptake inhibition is therapeutically
beneficial, comprising administering to a subject a therapeutically
effective amount of a composition of claim 19.
21. The method of claim 20, wherein the disorder comprises at least
one of depression, an anxiety disorder, attention deficit disorder,
attention deficit disorder with hyperactivity, bipolar and manic
conditions, bulimia, obesity or weight gain, narcolepsy, chronic
fatigue syndrome, seasonal affective disorder, premenstrual
syndrome, substance addiction or abuse, and nicotine addiction.
22. The method of claim 20, wherein the treatment is for reducing
clinical symptoms of affective disorders selected from dysphoric
mood or pervasive loss of interest or pleasure, accompanied by a
number of the following symptoms: sleep and appetite disturbances,
loss of energy, diminishment of sex drive, onset of body aches or
pains, memory loss, inability to make decisions, feelings of
self-reproach or excessive or inappropriate guilt, suicidal
thoughts, and reduced ability to concentrate.
23. The method of claim 20, wherein the disorder comprises reactive
depression, endogenous depression, or manic depression.
24. The method of claim 20, wherein the disorder, dysfunction, or
disease is selected from one or more of sexual dysfunction, eating
disorders, substance abuse, cerebrovascular disorder, vascular
disorder, obsessive-compulsive disease, anxiety, dementia, or
canine affective aggression.
25. The method of claim 20, wherein the disorder, dysfunction, or
disease comprises premature ejaculation or erectile
dysfunction.
26. The method of claim 20, wherein the disorder, dysfunction, or
disease comprises bulimia or anorexia nervosa.
27. The method of claim 20, wherein the treatment prevents or
alleviates one or more symptoms caused by withdrawal or partial
withdrawal from use of tobacco or nicotine.
28. A method of claim 20, wherein the disorder, dysfunction, or
disease is a cerebrovascular disorder caused by cerebral
infarction, cerebral hemorrhage, cerebral arteriosclerosis,
subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism,
ischemic, amnesia, or multi infarct dementia.
29. The method of claim 20, wherein the disorder, dysfunction, or
disease is a vascular disorder selected from myocardial infarction,
angina, stroke, pulmonary embolism, transient ischemic attack, deep
vein thrombosis, thrombotic re-occulusion subsequent to a coronary
intervention procedure, heart surgery or vascular surgery,
peripheral vascular thrombosis, Syndrome X, heart failure, or a
disorder in which a narrowing of at least one coronary artery
occurs.
30. A method of claim 29, wherein the subject is at risk for a
vascular event, disease or disorder, and the treatment reduces the
risk of occurrence of the vascular event.
31. A pharmaceutical kit comprising (i) a pharmaceutical
composition of claim 19 and (ii) one or more therapeutic agent(s)
selected from antipsychotics, anticonvulsants, psychostimulants,
mood stabilizing agents, or central nicotine stimulating agents for
co-administration with (i).
32. The pharmaceutical kit of claim 31, wherein the agent is a
substrate for a cytochrome P450 enzyme selected from CYP1A2,
CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
33. The pharmaceutical kit of claim 31, wherein the agent is
selected from clozapine, theophylline, warfarin, imipramine,
mephenyloin, sparteine, amitriptyline, carbamazepine, triazolam,
benzodiazepine, risperidone, gabapentin, or lamotrigine.
34. A pharmaceutical dosage form comprising a therapeutically
effective amount of the pharmaceutical composition of claim 19.
35. The dosage form of claim 34, wherein said dosage form is a
tablet or a capsule or oral solution.
36. The dosage form of claim 34, wherein said dosage form is
adapted for intravenous infusion, transdermal delivery or oral
delivery.
37. The dosage form of claim 34, wherein the therapeutically
effective amount is ranges from 10 mg to 500 mg.
38. The dosage form of claim 34, wherein the therapeutically
effective amount ranges from 25 mg to 250 mg.
39. The dosage form of claim 34, wherein the therapeutically
effective amount ranges from 50 mg to 150 mg.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of copending
International Application No. PCT/US02/35408, filed on Nov. 5,
2002, published under International Publication Number WO 01/040121
on 15 May 2003, and claims priority from U.S. provisional
application Ser. No. 60/337,608, filed on Nov. 8, 2001. The entire
disclosures of both are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Citalopram 1 (CIT), an antidepressant of the selective
serotonin reuptake inhibitor (SSRI) type, is one of the most
selective of the SSRIs. As an SSRI, citalopram has been used to
treat CNS affective disorders such as depression, as well as
indications wherein inhibition of serotonin reuptake is desired.
These indications include anxiety, obsessive-compulsive disorders,
various phobias, borderline personality disorders, and bipolar
disorders. Citalopram has also been used for treatment of alcohol
and tobacco substance abuse or addictions. Citalopram possesses one
stereocenter, and therefore exists in (+) and (-) forms. Racemic
citalopram is commercially available in the US under the trade name
CELEXA. 1
[0003] In humans, biotransformation of citalopram has been
attributed (in vitro) to the specific human hepatic cytochrome
enzymes P450 4A, P450 2C19 and, to a minimal extent, P450 2D6
(Willets, 1999). Citalopram is stereoselectively metabolized in the
liver to the polar metabolites, partially by N-demethylation to
desmethylcitalopram 2 (DICT) and didesmethylcitalopram 3 (DDCIT),
as well as by deamination to a propanoic acid metabolite 4
(CIT-PROP) and by N-oxidation to CIT-N-oxide (Baumann et al, 1995).
Importantly, neither citalopram nor its metabolite
desmethylcitalopram inhibit the activity of these or other
cytochrome P450 enzymes (P450 1A2, P450 2C9, P450 2E1) by more than
a mild degree. Citalopram's negligible affinity for receptors for
various neurotransmitters (e.g., acetylcholine, histamine,
norepinephrine, and dopamine), enzymes (e.g., monoamine oxidase),
and other reuptake sites (dopamine and norepinephrine) is thought
to account for its relative safety and tolerability, as well as its
growing popularity among physicians prescribing antidepressants
(Willets, 1999). Furthermore, citalopram's negligible effects on
P450 enzymes contribute to the drug's safety in view of drug-drug
interactions with other substrates.
SUMMARY OF THE INVENTION
[0004] The present invention relates to novel compositions of
matter containing enantiomerically enriched
(-)-desmethylcitalopram, (-)- and (+)-didesmethylcitalopram or
mixtures thereof or metabolites thereof in optimal ratios. Such
compositions possess potent serotonin reuptake inhibitory activity,
with minimal inhibitory effects on the reuptake of other known
monoamines, e.g., norepinephrine (NE) or dopamine (DA). Although
(-)-desmethylcitalopram possesses less serotonin reuptake
inhibitory property than its parent citalopram, the data disclosed
herein clearly indicate that both it and its immediate downstream
metabolite, (-)- and (+)-didesmethylcitalopram, retain considerable
serotonin reuptake inhibitory activity. Furthermore, their
half-lives are measurably longer compared to citalopram (Sanchez
and Hyttel 1999). These pharmacokinetic properties could make
(-)-CIT, (-)-DCIT, (+)-DDCIT or (-)-DDCIT more appropriate for
long-term therapy than the racemic or single enantiomer forms of
citalopram currently under development.
[0005] Reactive, endogenous, and manic depressions are CNS
affective disorders for which serotonin reuptake inhibitors are
particularly effective. Accordingly the present invention discloses
a method for treating depression and CNS affective disorders with
pharmaceutical compositions described herein. The methods described
herein are also useful for treating or preventing other CNS
disorders, cerebrovascular dysfunctions, or vascular dysfunctions,
sexual dysfunctions, eating disorders, and substance abuse. The
invention also provides a method for co-treatment of the
aforementioned disorders, dysfunctions, diseases, or syndromes with
antipsychotic, anti-anxiety, or mood-stabilizing agents without
compromising the pharmacological/therapeutic effects of the
individual pharmaceutical agent in the co-treatment regime. Agents
amenable to such a regime include, but are not limited to,
clozapine, risperidone, benzodiazepine, or gabapentine.
DETAILED DESCRIPTION OF THE INVENTION
[0006] A. Overview
[0007] The present invention discloses compositions and methods for
treating disease states associated with serotonergic dysfunctions.
In particular the present invention relates to novel compositions
of matter containing enantiomerically enriched
(-)-desmethylcitalopram, (-)- and (+)-didesmethylcitalopram or
mixtures thereof or metabolites thereof in optimal ratios. The
present invention also discloses methods for treating affective
disorders, namely depression. Additionally, the present invention
discloses methods for treating disease states where serotonin
reuptake inhibition would be beneficial. These disease states
include disorders or dysfunctions of the CNS, cerebrovascular, or
vascular systems.
[0008] B. Definitions
[0009] As used herein, the terms "citalopram" or "CIT" mean the
racemic compound shown in Formula 1, which is chemically known as
(.+-.)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofu-
ran-5-carbonitrile. 2
[0010] As used herein, the terms "desmethylcitalopram" or "DCIT"
mean the racemic or enantiomerically enriched compound shown in
Formula 2 which is chemically known as
(.+-.)-1-(3-methylaminopropyl)-1-(4-fluorophenyl)-1,3-
-dihydroisobenzofuran-5-carbonitrile. 3
[0011] As used herein, the terms "didesmethylcitalopram" or "DDCIT"
mean the racemic or enantiomerically enriched compound shown in
FIG. 3 which is chemically known as
(.+-.)-1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-di-
hydroisobenzofuran-5-carbonitrile. 4
[0012] As used herein, the terms "citalopram propanoic acid" or
"CIT-PROP" mean the racemic or enantiomerically enriched compound
shown in Formula 4 which is chemically known as
(.+-.)-1-(3-propanoic)-1-(4-fluorophenyl)-1,-
3-dihydroisobenzofuran-5-carbonitrile. 5
[0013] As used herein the term "citalopram metabolites"
encompasses, but is not limited to, mammalian metabolites of
racemic citalopram. In particular, the term "citalopram
metabolites" includes (.+-.) desmethylcitalopram, (.+-.)
didesmethylcitalopram, or citalopram propanoic acid.
[0014] As used herein, the term "affective disorder" refers to a
mental disorder characterized by a disturbance in the regulation of
mood, behavior and affect. This disorder includes, but is not
limited to, depression, anxiety disorders, attention deficit
disorder, attention deficit disorder with hyperactivity, bipolar
and manic conditions, bulimia, obesity or weight gain, narcolepsy,
chronic fatigue syndrome, seasonal affective disorder, premenstrual
syndrome, substance addiction or abuse, and nicotine addiction. A
major feature of the clinical picture of affective disorders is
dysphoric mood or pervasive loss of interest or pleasure,
accompanied by a number of the following symptoms: sleep and
appetite disturbances, loss of energy, diminishment of sex drive,
onset of body aches or pains, memory loss, inability to make
decisions, feelings of self-reproach or excessive or inappropriate
guilt, suicidal thoughts, and reduced ability to concentrate.
[0015] As used herein, a therapeutic that "prevents" a disorder or
condition refers to a compound that, in a statistical sample,
reduces the occurrence of the disorder or condition in the treated
sample relative to an untreated control sample, or delays the onset
or reduces the severity of one or more symptoms of the disorder or
condition relative to the untreated control sample.
[0016] As used herein, the term "a method for treating vascular
disorders" means relief from the disorders of the vascular system
including, but not limited to, myocardial infarction, angina,
stroke, pulmonary embolism, transient ischemic attack, deep vein
thrombosis, thrombotic re-occulusion subsequent to a coronary
intervention procedure, heart surgery or vascular surgery,
peripheral vascular thrombosis, Syndrome X, heart failure, or a
disorder in which a narrowing of at least one coronary artery
occurs.
[0017] As used herein, the term "a method of treating serotonergic
dysfunctions" means relief from symptoms of a disruption of
serotonin neurotransmission manifesting in neurodegenerative
diseases as well as other diseases affecting spinal and supraspinal
regulation of motor control, the central nervous system including
regulation of sensory, autonomic, cognitive, and affective
functions, vascular system, cerebrovascular systems or the
integrity of the blood brain-barrier.
[0018] As used herein, the term "a method of treating depression"
means relief from the symptoms of depression which include, but are
not limited to, changes in mood, feelings of intense sadness,
despair, mental slowing, loss of concentration, pessimistic worry,
agitation, and self-deprecation. Physical changes may also be
relieved, including insomnia, anorexia, weight loss, decreased
energy and libido, and abnormal hormonal circadian rhythms.
[0019] As used herein, the term "a method for treating sexual
dysfunction" relief from symptoms of including, but not limited to
loss of sexual desire, sexual arousal disorder, inability to obtain
or maintain an erection, premature ejaculation, absence of
emission, or inability to achieve erection correlated with
endocrine, drug, local, neurologic, or vascular causes.
[0020] As used herein, the term "a method for treating cerebral
function disorders" means relief from disease states associated
with cerebral function disorders involving intellectual deficits
which include, but are not limited to, senile dementia, Alzheimer's
type dementia, memory loss, amnesia/amnestic syndrome, disturbances
of consciousness, coma, lowering of attention, speech disorders,
Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome
and schizophrenia. Also within the meaning of cerebral function
disorders are disorders caused by cerebrovascular diseases
including, but not limited to, cerebral infarction, cerebral
bleeding, cerebral arteriosclerosis, cerebral venous thrombosis,
head injuries, and the like and where symptoms include disturbances
of consciousness, senile dementia, coma, diminished of attention,
speech disorders, and the like.
[0021] The terms "substance abuse", "pre-menstrual syndrome",
"anxiety", "panic disorder endogenous depression", "sleep
disorders", "borderline personality disorders", "post-traumatic
stress disorders", and "eating disorders" are used herein in a
manner consistent with their accepted meanings in the art. See,
e.g., Diagnostic and Statistical Manual of Mental Disorders,
4.sup.th Ed., American Psychiatric Association, (1997)
(DSM-IV.TM.). The terms "method of treating or preventing", "method
of treating", and "method of preventing" when used in connection
with these disorders mean the amelioration, prevention, or relief
from the symptoms and/or effects associated with these disorders.
Without being limited by any theory, the treatment or prevention of
certain of these disorders may be related to the activity of the
active ingredient(s) as inhibitors of serotonin reuptake.
[0022] The term "healthcare providers" refers to individuals or
organizations that provide healthcare services to a person,
community, etc. Examples of "healthcare providers" include doctors,
hospitals, continuing care retirement communities, skilled nursing
facilities, subacute care facilities, clinics, multispecialty
clinics, freestanding ambulatory centers, home health agencies, and
HMO's.
[0023] The term "as valence and stability permits" in reference to
compounds disclosed herein refers to compounds that have in vitro
or in vivo half-lives at room temperature of at least 12 hours, or
at least 24 hours, and are preferably capable of being stored at
0.degree. C. for a week without decomposing by more than about
10%.
[0024] The term "clathrate" refers to inclusion compounds in which
the guest molecule is in a cage formed by the host molecule or by a
lattice of host molecules.
[0025] As used in this disclosure, "enantiomerically enriched"
refers to products whose enantiomeric excess is greater than zero.
Enantiomeric excess (ee) is the "excess" of one enantiomer over the
other. As a result, since both enantiomers are present in equal
amounts in a racemic mixture, the enantiomeric excess would be zero
(0% ee). However, if one enantiomer were enriched such that it
constitutes 95% of the product, then the enantiomeric excess would
be 90% ee (95%-5% (the amount of the enriched enantiomer minus the
amount of the other enantiomer)). In general, higher enantiomeric
purity (>about 50% ee) is preferred, with enantiomeric excess of
between about 75% ee and about 90% ee being more preferred, and
enantiomeric excess of greater than about 90% ee being particularly
preferred.
[0026] The term "enantiomerically pure" refers to a compound
wherein the enantiomeric excess is about 100%.
[0027] The terms "half-life" or "half-lives" refer to the time
required for half of a quantity of a substance to be converted to
another chemically distinct species in vitro or in vivo.
[0028] The term "metabolic derivative" refers to a compound derived
by one or more in vitro or in vivo enzymatic transformations on the
parent compound, wherein the resulting derivative has an ED.sub.50
value as a serotonin reuptake inhibitor that is less than
1000.times.ED.sub.50 value of the parent compound. The term
"ED.sub.50" means the dose of a drug that produces 50% of its
maximum response or effect.
[0029] The term "prodrug" refers to any compound that is converted
to a more pharmacologically active compound under physiological
conditions (i.e., in vivo). A common method for making a prodrug is
to select moieties that are hydrolyzed under physiological
conditions to provide the desired biologically active drug.
[0030] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent
methyl, ethyl, phenyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl,
respectively. A more comprehensive list of the abbreviations
utilized by organic chemists of ordinary skill in the art appears
in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled
Standard List of Abbreviations. The abbreviations contained in said
list, and all abbreviations utilized by organic chemists of
ordinary skill in the art are hereby incorporated by reference.
[0031] Certain compounds of the present invention may exist in
particular geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
(-)- and (+)-enantiomers, diastereomers, (D)-isomers, (L)-isomers,
the racemic mixtures thereof, and other mixtures thereof, as
falling within the scope of the invention. Additional asymmetric
carbon atoms may be present in a substituent such as an alkyl
group. All such isomers, as well as mixtures thereof, are intended
to be included in this invention.
[0032] If, for instance, a particular enantiomer of a compound of
the present invention is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts may be formed with an appropriate
optically active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0033] As herein used, the term "chiral ligand" is well known in
the art and means one or more chiral chemical compounds of organic,
inorganic or organometallic nature that is present in a reaction
covalently or ionically bonded to one or more reagents, or is a
catalytic or quantitative reagent on its own, designed to
facilitate enantiomeric excess induction in a reaction which would
otherwise produce racemic products. Known ligands suitable for the
present invention include, but are not limited to, substituted or
unsubstituted binaphthyls, alkylphosphines, arylphosphines,
aziridines, diols, amino alcohols, alkylpyrrolidines, aryl
pryrrolidines, diamines, aminoacids, carbohydrates, oxazolines, or
phosphinoalkyloxazolines.
[0034] Contemplated equivalents of the compounds described above
include compounds which otherwise correspond thereto, and which
have the same general properties thereof (e.g., the ability to
inhibit serotonin reuptake), wherein one or more simple variations
of substituents are made which do not adversely affect the efficacy
of the compound. In general, the compounds of the present invention
may be prepared by the methods illustrated in the general reaction
schemes as, for example, described below, or by modifications
thereof, using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are in themselves known, but
are not mentioned here.
[0035] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover. Also for purposes of this invention, the term
"hydrocarbon" is contemplated to include all permissible compounds
having at least one hydrogen and one carbon atom. In a broad
aspect, the permissible hydrocarbons include acyclic and cyclic,
branched and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic organic compounds which can be substituted or
unsubstituted.
[0036] C. Exemplary Embodiments
[0037] The invention relates to racemic or enantiomerically
enriched pharmaceutical compositions of a citalopram metabolite
other than (+)-desmethylcitalopram. In particular the invention
relates to racemic or enantiomerically pure pharmaceutical
compositions of (-)-desmethylcitalopram, or enantiomerically
enriched (+)-didesmethylcitalopram or (-)-didesmethylcitalopram.
This invention further relates to the synthesis of racemic or
enantiomerically pure or enriched citalopram metabolites and to
compositions (e.g. pharmaceutical compositions) comprising them.
The invention also relates to novel uses of the compounds disclosed
herein, which constitute improvements over the use of the racemic
citalopram as well as improvements over the optically pure (+)
isomer of citalopram.
[0038] One embodiment of the invention relates to compounds having
structures depicted in Formula I. 6
[0039] Another embodiment of the invention relates to compounds
having structures depicted in Formula II: 7
[0040] In one embodiment of the invention, the composition
comprises, individually or in combination, (-)-desmethylcitalopram,
(-)-didesmethylcitalopram, (+)-didesmethylcitalopram. In one
embodiment, the amount of the (-)-desmethyl, (-)-didesmethyl,
(+)-didesmethyl metabolite of citalopram comprises greater than
about 1%, 5%, 10%, 25%, 50%, 75%, or even 90% by weight of the
composition.
[0041] Another aspect of the invention encompasses a method for
preparing racemic desmethylcitalopram which comprises contacting,
preferably sequentially, the commercially available phthalide with
two Grignard reagents, followed by effecting ring closure, acidic
hydrolysis, and a subsequent reductive amination step, as shown in
Scheme 1. The preferred Grignard reagents are 4-fluorophenyl
magnesium bromide and ethyldioxolane magnesium bromide. In certain
embodiments, the reagent used to effect ring closure is mesyl
chloride. The preferred reagents for reductive amination are
methylamine and sodium borohydride. In one embodiment of the
invention the resultant amine is isolated as is or is reacted with
an acid to form a salt or with a metal to form a metal complex.
[0042] In one embodiment, the acid used is L-tartaric acid.
[0043] In another embodiment of the invention any or all steps of
the synthesis are carried out on a solid support or in a
combinatorial fashion. 89
[0044] Another embodiment of the invention encompasses a method for
preparing enantiomerically enriched (-)-desmethylcitalopram and
(+)-desmethylcitalopram which comprises contacting the commercially
available phthalide with two Grignard reagents, wherein the second
Grignard reagent would use a chiral ligand (by screening many to
obtain one with high ee) to give the enantiomerically enriched
tertiary alcohol. Ring closure and subsequent reaction are as shown
in Scheme 2. In one embodiment of the invention, the resultant
amine is isolated as is or is reacted with an acid to form a salt
or with a metal to form a metal complex. In one embodiment, the
acid used is L-tartaric acid.
[0045] In one embodiment of the invention any or all steps of the
synthesis are carried out on a solid support or in a combinatorial
fashion. 1011
[0046] Another embodiment of the invention encompasses a method for
preparing enantiomerically enriched (-)-desmethylcitalopram and
(+)-desmethylcitalopram including chiral column chromatography
resolution of the racemic ketal 6. In one embodiment, a CHIRALCEL
OD=column with methanol as eluent is used to resolve the
corresponding enantiomers (6a and 6b) as shown in Scheme 3.
Subsequent reactions of compound 6a and 6b are the same as in
Scheme 2. 12
[0047] Another embodiment of the invention encompasses a method for
preparing racemic didesmethylcitalopram by reductive amination of
aldehyde 7 with an ammonia equivalent followed by hydride reduction
as shown in Scheme 4. The resultant product can be isolated as a
salt. The preferred ammonia equivalent is (-)-tert-butylsulfinamide
which is contacted with aldehyde 7 in the presence of an alkoxy
titanium reagent. The preferred reductant is sodium borohydride. In
one embodiment of the invention, the resultant amine is isolated as
is or is reacted with an acid to form a salt or with a metal to
form a metal complex. In one embodiment, the acid used to prepare a
salt is L-tartaric acid. In one embodiment of the invention, any or
all steps of the synthesis are carried out on a solid support or in
a combinatorial fashion. 13
[0048] Another embodiment of the invention encompasses a method for
preparing enantiomerically enriched didesmethylcitalopram by
derivatizing racemic didesmethylcitalopram with BOC-anhydride,
followed by column chromatography resolution of the racemic
BOC-didesmethylcitalopram as shown in Scheme 5. Subsequent acidic
hydrolysis of the BOC-derivatized enantiomers yields
enantiomerically enriched didesmethylcitalopram. The preferred
separation conditions are CHIRALCEL OD column with methanol as
eluent. 14
[0049] Another embodiment of the invention encompasses a versatile
method for preparing enantiomerically enriched metabolites of
citalopram by contacting aldehyde 7 with a variety of reagents as
shown in Scheme 6. 15
[0050] In an embodiment of the present invention, the compositions
used in this invention selectively inhibit serotonin reuptake over
reuptake of other monoamine neurotransmitters. In one embodiment,
the compositions selectively inhibit serotonin reuptake over
reuptake of dopamine or norepinephrine. In a still further
preferred embodiment, the compositions used in this invention have
IC.sub.50's for inhibition of serotonin reuptake that are more than
two orders of magnitude lower than the corresponding IC.sub.50 for
inhibition of dopamine or norepinephrine reuptake.
[0051] One embodiment of the invention encompasses a method of
treating a subject in need of such treatment with a therapeutically
effective amount of enantiomerically pure (-)-desmethylcitalopram,
or enantiomerically enriched (+) didesmethylcitalopram, or
(-)-didesmethylcitalopram, a combination thereof, or a
pharmaceutically acceptable salt, solvate, or clathrate thereof.
The aforementioned citalopram metabolites can be used to treat
serotonergic dysfunctions while exhibiting longer half lives than
citalopram. While it is possible for a compound of the present
invention to be administered alone, it is preferable to administer
the compound as a pharmaceutical formulation (composition). The
composition of the invention may be formulated for administration
in any convenient way for use in human or veterinary medicine. In
certain embodiments, the compound included in the pharmaceutical
preparation may be active itself, or may be a prodrug of
(-)-desmethylcitalopram, (+)-didesmethylcitalopram- , or
(-)-didesmethylcitalopram, which can be converted to an active
compound in a physiological setting.
[0052] Thus, another aspect of the present invention provides
pharmaceutically acceptable compositions comprising a
therapeutically effective amount of one or more of the compounds
described herein, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specially formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular or intravenous injection as, for example, a sterile
solution or suspension; (3) topical application, for example, as a
cream, ointment or spray applied to the skin; or (4) intravaginally
or intrarectally, for example, as a pessary, cream or foam.
However, in certain embodiments the subject compounds may be simply
dissolved or suspended in sterile water. In certain embodiments,
the pharmaceutical preparation is non-pyrogenic, i.e., does not
substantially elevate the body temperature of a patient.
[0053] One embodiment of the invention is a pharmaceutical dosage
form comprising a therapeutically effective amount of
enantiomerically pure desmethyl or enantiomerically enriched
didesmethyl metabolite of citalopram or a pharmaceutically
acceptable salt, solvate, or clathrate or pharmaceutical excipient
thereof. In one preferred embodiment, the dosage form is a tablet
or a capsule or oral solution. In one embodiment, the dosage is
adapted for intravenous infusion, transdermal delivery or oral
delivery. In one embodiment a therapeutically effective amount of
the dosage is from about 10 mg to about 500 mg. In one embodiment,
the dosage is from about 25 mg to about 250 mg. In a still further
preferred embodiment, the dosage is from about 50 mg to about 150
mg.
[0054] One embodiment of the invention is a method for treating
affective disorders and reducing the clinical symptoms associated
with affective disorders. In certain embodiments the particular
affective disorders are comprised of reactive depression,
endogenous depression and manic depression, anxiety disorders,
attention deficit disorder, attention deficit disorder with
hyperactivity, bipolar and manic conditions, bulimia, obesity or
weight gain, narcolepsy, chronic fatigue syndrome, seasonal
affective disorder, premenstrual syndrome, substance addiction or
abuse, and nicotine addiction. In other embodiments the clinical
symptoms include dysphoric mood or pervasive loss of interest or
pleasure, accompanied by a number of the following symptoms: sleep
and appetite disturbances, loss of energy, diminishment of sex
drive, onset of body aches or pains, memory loss, inability to make
decisions, feelings of self-reproach or excessive or inappropriate
guilt, suicidal thoughts, and reduced ability to concentrate.
[0055] Thus, the invention encompasses a method of treating CNS
affective disorders in a subject which comprises administering to a
subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0056] Another embodiment of the invention encompasses method for
treating cerebral function disorders. Such disorders include, but
are not limited to, amnesia, dementia, Alzheimer's type dementia,
psychosis, sleep disorders, post-traumatic stress disorders,
borderline personality disorder, trichotillomania, or panic
disorder. Cerebral function disorders may be induced by factors
including, but not limited to, cerebrovascular diseases such as
cerebral infarction, cerebral venous thrombosis, head injuries, and
the like, and where symptoms include disturbances of the
consciousness, senile dementia, coma, lowering of attention, speech
disorders, and the like. Thus, the invention encompasses a method
of treating a cerebral function disorder in a subject which
comprises administering to a subject in need of such treatment a
therapeutically effective amount of a citalopram metabolite, or a
mixture or a pharmaceutically acceptable salt, solvate, or
clathrate thereof.
[0057] Another embodiment of the invention is a method for treating
vascular disorders which comprises administering to a subject in
need of such treatment a therapeutically effective amount of a
citalopram metabolite, or a mixture or a pharmaceutically
acceptable salt, solvate, or clathrate thereof.
[0058] Another embodiment of the invention is a method for treating
sexual dysfunction such as, but not limited to, premature
ejaculation or erectile dysfunction, which comprises administering
to a subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0059] Another embodiment of the invention is a method for treating
premenstrual syndrome, which comprises administering to a subject
in need of such treatment a therapeutically effective amount of a
citalopram metabolite, or a mixture or a pharmaceutically
acceptable salt, solvate, or clathrate thereof.
[0060] Another embodiment of the invention is a method for treating
anxiety, which comprises administering to a subject in need of such
treatment a therapeutically effective amount of a citalopram
metabolite, or a mixture or a pharmaceutically acceptable salt,
solvate, or clathrate thereof.
[0061] Another embodiment of the invention is a method for treating
eating disorders, including but not limited to bulimia and
anorexia, which comprises administering to a subject in need of
such treatment a therapeutically effective amount of a citalopram
metabolite, or a mixture or a pharmaceutically acceptable salt,
solvate, or clathrate thereof.
[0062] Another embodiment of the invention is a method for treating
obsessive compulsive disease, which comprises administering to a
subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0063] Another embodiment of the invention is a method of treating,
preventing or alleviating one or more symptoms caused by partial
withdrawal form tobacco or nicotine, which comprises administering
to a subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0064] Another embodiment of the invention is a method of treating,
preventing cerebrovascular disorder which comprises administering
to a subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate thereof. In
certain embodiments the disorder results from cerebral infarction,
cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid
hemorrhage, cerebral thrombosis, or cerebral embolism. In other
embodiments the disorder is ischemia, amnesia associated with
ischemia, or vascular or multi infarct dementia.
[0065] Another embodiment of the invention is a method of treating,
preventing vascular disorder which comprises administering to a
subject in need of such treatment a therapeutically effective
amount of a citalopram metabolite, or a mixture or a
pharmaceutically acceptable salt, solvate, or clathrate thereof. In
certain embodiments the disorder is selected form myocardial
infarction, angina, stroke, pulmonary embolism, transient ischemic
attack, deep vein thrombosis, thrombotic re-occulusion subsequent
to a coronary intervention procedure, heart surgery or vascular
surgery, peripheral vascular thrombosis, Syndrome X, heart failure,
or a disorder in which a narrowing of at least one coronary artery
occurs. In certain embodiments, the present invention provides a
method for treating a subject at risk for vascular event, disease,
or disorder so as to reduce the risk of occurrence of the vascular
event, wherein the vascular event is comprised of the
aforementioned manifestations of a vascular disorder.
[0066] Another embodiment of the invention is a method of
co-administration of the pharmaceutical compositions described
herein with another agent selected from an antipsychotic,
anticonvulsant, mood stabilizing agent, or a central nicotine
stimulating agent. Examples of drugs amenable for co-treatment
include clozapine, therophylline, warfarine, imipramine,
mephenyloin, sparteine, amitriptyline, carbamazepine, triazolam,
benzodiazepine, risperidone, gabapentin, and lamotrigine.
Alternatively, the co-administered agent may be a substrate for a
cytochrome P450 enzyme selected from CYP1A2, CYP2C9, CYP2C19,
CYP2D6, or CYP3A4.
[0067] Enantiomerically pure or enriched (-)-desmethylcitalopram,
or enantiomerically enriched didesmethylcitalopram is intended to
provide an improvement in the treatment of such disorders because
they exhibit longer half lives than citalopram.
[0068] Another aspect of the present invention is a method for
conducting a pharmaceutical business, comprising:
[0069] a. manufacturing a pharmaceutical composition disclosed
herein; and
[0070] b. marketing to healthcare providers the benefits of using
the composition in the treatment one or more disorders,
dysfunctions, or diseases for which serotonin reuptake inhibition
is therapeutically beneficial.
[0071] In one embodiment, the present invention provides a method
for conducting a pharmaceutical business, comprising:
[0072] a. providing a distribution network for selling a
pharmaceutical composition disclosed herein; and
[0073] b. marketing to healthcare providers the benefits of using
the composition in the treatment one or more disorders,
dysfunctions, or diseases for which serotonin reuptake inhibition
is therapeutically beneficial.
[0074] In another embodiment, the present invention provides a
method for conducting a pharmaceutical business, comprising:
[0075] a. determining an appropriate formulation and dosage of a
pharmaceutical composition disclosed herein, singly or in
combination with one or more therapeutic agent(s) selected from
antipsychotics, anticonvulsants, psychostimulants, mood stabilizing
agents, or central nicotine stimulating agents;
[0076] b. conducting therapeutic profiling of formulations
identified in step (a), for efficacy and toxicity in animals;
and
[0077] c. providing a distribution network for selling a
preparation or preparations identified in step (b) as having an
acceptable therapeutic profile.
[0078] In certain embodiments, the pharmaceutical business method
disclosed in the present invention includes an additional step of
providing a sales group for marketing the preparation to healthcare
providers. Another embodiment of the present invention provides a
method for conducting a pharmaceutical business, comprising:
[0079] a. determining an appropriate formulation and dosage of a
pharmaceutical composition disclosed herein, singly or in
combination with one or more therapeutic agent(s) selected from
antipsychotics, anticonvulsants, psychostimulants, mood stabilizing
agents, or central nicotine stimulating agents; and
[0080] b. licensing, to a third party, the rights for further
development and sale of the formulation.
[0081] D. Pharmacological Formulations
[0082] In another aspect, the present invention provides
pharmaceutical compositions. The composition for use in the subject
method may be conveniently formulated for administration with a
biologically acceptable medium, such as water, buffered saline,
polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycol and the like) or suitable mixtures thereof. The
optimum concentration of the active ingredient in the chosen medium
can be determined empirically, according to procedures well known
to medicinal chemists. As used herein, "biologically acceptable
medium" includes any and all solvents, dispersion media, and the
like which may be appropriate for the desired route of
administration of the pharmaceutical preparation. The use of such
media for pharmaceutically active substances is known in the art.
Except insofar as any conventional media or agent is incompatible
with the activity of the serotonin reuptake inhibition, its use in
the pharmaceutical preparation of the invention is contemplated.
Suitable vehicles and their formulation inclusive of other proteins
are described, for example, in the book Remington's Pharmaceutical
Sciences (Remington's Pharmaceutical Sciences. Mack Publishing
Company, Easton, Pa., USA 1985). These vehicles include injectable
"deposit formulations".
[0083] Pharmaceutical formulations of the present invention can
also include veterinary compositions, e.g., pharmaceutical
preparations of the serotonin reuptake inhibitor suitable for
veterinary uses, e.g., for the treatment of livestock or domestic
animals, e.g., dogs.
[0084] Methods of introduction may also be provided by rechargeable
or biodegradable devices. Various slow release polymeric devices
have been developed and tested in vivo in recent years for the
controlled delivery of drugs, including proteinaceous
biopharmaceuticals. A variety of biocompatible polymers (including
hydrogels), including both biodegradable and non-degradable
polymers, can be used to form an implant for the sustained release
of a drug at a particular target site.
[0085] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given by forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, controlled release
patch, etc.; administration by injection, infusion or inhalation;
topical by lotion or ointment; and rectal by suppositories. Oral
and topical administrations are preferred.
[0086] The phrases "parenteral administration" or "administered
parenterally" as used herein mean modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal, and intrasternal injection and
infusion.
[0087] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0088] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally, and topically, as
by powders, ointments or drops, including buccally and
sublingually.
[0089] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically acceptable
dosage forms such as described below or by other conventional
methods known to those of skill in the art.
[0090] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient effective to achieve
the desired therapeutic response for a particular patient,
composition, and mode of administration without being toxic to the
patient.
[0091] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion of the particular compound being employed, the
duration of the treatment, other drugs, compounds and/or materials
used in combination with the particular composition employed, the
age, sex, weight, condition, general health and prior medical
history of the patient being treated, and like factors well known
in the medical arts.
[0092] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0093] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, intravenous, intracerebroventricular and subcutaneous
doses of the compounds of this invention for a patient will range
from about 0.0001 to about 100 mg per kilogram of body weight per
day.
[0094] If desired, the effective daily dose of the active compound
may be administered daily in two, three, four, five, six or more
sub-doses administered separately at appropriate intervals,
optionally, in unit dosage forms. A physician or veterinarian
having ordinary skill in the art can readily determine the total
duration of the treatment regime.
[0095] The term "treatment" is intended to encompass also
prophylaxis, therapy and cure.
[0096] The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals such as
equines, cattle, swine and sheep; and poultry and pets in
general.
[0097] The compound of the invention can be administered as such or
in admixtures with pharmaceutically acceptable and/or sterile
carriers and can also be administered in conjunction with other
antimicrobial agents such as penicillins, cephalosporins,
aminoglycosides and glycopeptides. Conjunctive therapy, thus
includes sequential, simultaneous and separate administration of
the active compound in a way that the therapeutical effects of the
first administered drug are not entirely past when the subsequent
drug is administered.
[0098] The phrase "therapeutically effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect by inhibition of
serotonin reuptake in at least a sub-population of cells in an
animal and thereby blocking the biological consequences of that
pathway in the treated cells, at a reasonable benefit/risk ratio
applicable to any medical treatment.
[0099] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0100] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting the subject antagonists from one organ, or portion of
the body, to another organ, or portion of the body. Each carrier
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not injurious to the
patient. Some examples of materials which can serve as
pharmaceutically acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its metabolites, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (H) polyols, such as glycerin, sorbitol, mannitol
and polyethylene glycol; (12) esters, such as ethyl oleate and
ethyl laurate; (13) agar; (14) buffering agents, such as magnesium
hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations.
[0101] As set out above, certain embodiments of the present
composition may contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable acids. The term
"pharmaceutically acceptable salts" in this respect refers to the
relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present invention. These salts can be prepared in
situ during the final isolation and purification of the compounds
of the invention, or by separately reacting a purified compound of
the invention in its free base form with a suitable organic or
inorganic acid, and isolating the salt thus formed. Representative
salts include the hydrobromide, hydrochloride, sulfate, bisulfate,
phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,
laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,
fumarate, besylate, succinate, tartrate, napthylate, mesylate,
glucoheptonate, lactobionate, and laurylsulphonate salts and the
like. (See, for example, Berge et al. (1977) "Pharmaceutical
Salts", J. Pharm. Sci. 66:1-19)
[0102] The pharmaceutically acceptable salts of the subject
compounds include the conventional nontoxic salts or quaternary
ammonium salts of the compounds, e.g., from non-toxic organic or
inorganic acids. For example, such conventional nontoxic salts
include those derived from inorganic acids such as hydrochloride,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like.
[0103] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically acceptable salts with pharmaceutically
acceptable bases. The term "pharmaceutically acceptable salts" in
these instances refers to the relatively non-toxic, inorganic and
organic base addition salts of compounds of the present invention.
These salts can likewise be prepared in situ during the final
isolation and purification of the compounds, or by separately
reacting the purified compound in its free acid form with a
suitable base, such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation, with ammonia, or with a
pharmaceutically acceptable organic primary, secondary or tertiary
amine. Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like. (See, for example, Berge et al., supra)
[0104] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0105] Examples of pharmaceutically acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0106] Pharmacological dosages or formulations of the present
invention include those suitable for oral, nasal, topical
(including buccal and sublingual), rectal, vaginal and/or
parenteral administration. The dosages may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of active ingredient
which can be combined with a carrier material to produce a single
dosage form will vary depending upon the host being treated, the
particular mode of administration. The amount of active ingredient
which can be combined with a carrier material to produce a single
dosage form will generally be that amount of the compound which
produces a therapeutic effect. Generally, out of one hundred
percent, this amount will range from about 1 percent to about
ninety-nine percent of active ingredient, preferably from about 5
percent to about 70 percent, most preferably from about 10 percent
to about 30 percent.
[0107] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0108] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouthwashes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0109] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate
or dicalcium phosphate, and/or any of the following: (1) fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, cetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) coloring agents. In the case of capsules, tablets
and pills, the pharmaceutical compositions may also comprise
buffering agents. Solid compositions of a similar type may also be
employed as fillers in soft and hard-filled gelatin capsules using
such excipients as lactose or milk sugars, as well as high
molecular weight polyethylene glycols and the like.
[0110] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0111] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0112] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0113] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0114] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0115] It is known that sterols, such as cholesterol, will form
complexes with cyclodextrins. Thus, in preferred embodiments, where
the inhibitor is a steroidal alkaloid, it may be formulated with
cyclodextrins, such as .alpha.-, .beta.- and .gamma.-cyclodextrin,
dimethyl-.beta.cyclodextrin and
2-hydroxypropyl-.beta.-cyclodextrin.
[0116] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active ingredient.
[0117] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0118] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0119] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose metabolites, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0120] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0121] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
composition in the proper medium. Absorption enhancers can also be
used to increase the flux of the composition across the skin. The
rate of such flux can be controlled by either providing a rate
controlling membrane or dispersing the compound in a polymer matrix
or gel.
[0122] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0123] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more pharmaceutically
acceptable sterile isotonic aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, or sterile powders which may
be reconstituted into sterile injectable solutions or dispersions
just prior to use, which may contain antioxidants, buffers,
bacteriostats, solutes which render the formulation isotonic with
the blood of the intended recipient or suspending or thickening
agents.
[0124] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0125] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents which delay
absorption such as aluminum monostearate and gelatin.
[0126] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0127] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0128] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99.5% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0129] The addition of the active compound of the invention to
animal feed is preferably accomplished by preparing an appropriate
feed premix containing the active compound in an effective amount
and incorporating the premix into the complete ration.
[0130] Alternatively, an intermediate concentrate or feed
supplement containing the active ingredient can be blended into the
feed. The way in which such feed premixes and complete rations can
be prepared and administered are described in reference books (such
as "Applied Animal Nutrition", W.H. Freedman and CO., San
Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B
books, Corvallis, Ore., U.S.A., 1977).
EXAMPLES
Example 1
[0131] Synthesis of
4-[3-[1,3]-dioxolan-2-yL-1-(4-fluorophenyl)-1-hydroxyp-
ropyl]-3-hydroxymethylbenzonitrile (5): To a suspension of
1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile 5 (15 g) in THF (50
mL, anhydrous) at 5-10.degree. C. under argon was added
4-flurophenylmagnisum bromide in ethyl ether (50 ml, 2 M). The
reaction mixture was warmed to room temperature and stirred for 5
h. At that time, a second Grignard reagent [prepared from
2-(2-bromoethyl)-[1,3]-dioxolane (25 g) with Mg powder in THF] was
added at room temperature. The reaction mixture was stirred at room
temperature for 14 h. The reaction mixture was then quenched at
0.degree. C. with aqueous ammonium chloride. The organic phase was
separated and washed with water (50 mL), and concentrated to give a
crude product. It was purified by flash chromatography (EtOAc:
Hexane 1:1) to give 17 g of the titled product 5. .sup.1H NMR
(CDCl.sub.3, .delta.): 8 1.54-1.66 (m, 1H), 1.75-1.88 (m, 1H),
2.18-2.30 (m, 1H), 2.36-2.47 (m, 1H), 356 (broad s, 1H), 3.80-4.00
(m, 4H), 4.10-4.17 (d, J=8 Hz, 1H), 4.22-4.30 (d, J=8 Hz, 1H), 4.86
(t, J=3 Hz, 1H), 5.50 (broad s, 1H), 6.8-7.10 (m, 2H), 7.16-7.26
(m, 2H), 7.50-7.70 (m, 3H). .sup.3C NMR(CDCl.sub.3, .delta.): 8
27.2, 35.8, 63.1, 64.9, 77.8, 103.4, 111.4, 114.7, 115.0, 118.3,
127.1, 127.6, 127.3, 131.1, 134.7, 141.1, 149.7, 159.9, 163.2.
Example 2
[0132] Synthesis of
1-(2-[1,3]-dioxolan-2-yL-ethyl)-1-(4-fluorophenyl)-1,3-
-dihydro-isobenzofuran-5-carbonitrile (6):
4-[3-[1,3]-dioxolan-2-yL-1-(4-f-
luorophenyl)-1-hydroxypropyl]-3-hydroxymethylbenzonitrile (15 g)
was dissolved in dichloromethane (150 mL) at room temperature,
followed by addition of triethylamine (25 mL). The reaction mixture
was cooled to 5-10.degree. C. and stirred for 5 min, followed by
addition of methane sulfonylchloride (8.4 g). The reaction mixture
was warmed to room temperature and stirred for 10 min. It was
quenched with 2% NaOH (100 mL) while maintained to 10-20.degree. C.
The organic phase was separated and was water, concentrated to give
19.2 g crude product. .sup.1H NMR (CDCl.sub.3, .delta.): 1.42-1.57
(m, 1H), 1.63-1.76 (m, 1H), 2.20-2.38 (m, 2H), 3.78-3.96 (m, 4H),
4.84 (t, J=3 Hz, 1H), 5.18 (m, 2H), 7.00 (m, 2H), 7.38-7.50 (m,
4H), 7.60 (m, 1H). 2 was separated to its enantiomer by CHIRALCEL
OD=column using Methanol as eluent. Enantiomer 8a, 6.67 min;
Enantiomer 8b, 8.30 min.
Example 3
[0133] Synthesis of
1-(4-fluorophenyl)-1-(3-Oxopropyl)-1,3-dihydro-isobenz-
ofuran-5-carbonitrile (7):
1-(2-[1,3]-dioxolan-2-yL-ethyl)-1-(4-fluorophen-
yl)-1,3-dihydro-isobenzofuran-5-carbonitrile (6 g) was dissolved in
a mixture of acetone (100 mL) and aqueous HCl (5 N, 30 mL). The
reaction mixture was stirred at room temperature for 60 h, and
concentrated to remove acetone. The aqueous solution was extracted
with ethyl acetate (40 mL), and concentrated to give a crude oil.
It was dissolved in acetone (80 mL) and aqueous HCl (SN, 25 mL),
stirred for 3 h, and concentrated to remove acetone. The aqueous
solution was extracted with ethyl acetate (40 mL), washed with
water, and concentrated to give the pure product 7 (5.6 g). .sup.1H
NMR (CDCl.sub.3, .delta.): 2.22-2.64 (m, 4H), 5.14 (s, 2H),
6.94-7.06 (m, 2H), 7.40-7.63 (m, 5H), 9.70 (s, 1H).
Example 4
[0134] Synthesis of 2-MethyL-propane-2-sulfinic acid
[3-[5-cyano-L-(4-flurophenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl]-ami-
de (8):
1-(4-fluorophenyl)-1-(3-Oxopropyl)-1,3-dihydro-isobenzofuran-5-car-
bonitrile (3.0 g) was dissolved in THF (20 mL), followed by
addition of (-)-tert-butylsulfinamide (1.5 g), and Ti(OEt).sub.4
(20 mL, Aldrich) in EtOH. The reaction mixture was stirred at room
temperature for 10 min, and 55.degree. C. for 1 h. The reaction
mixture was cooled to 5-10.degree. C., was added brine (50 .mu.L),
and EtOAc (150 .mu.L). The reaction mixture was stirred at room
temperature for 10 min and filtered. The EtOAc layer in the
filtrate was separated and washed with brine and concentrated to
give a crude oil. It was dissolved in THF (20 ml), cooled to
5-10.degree. C. and added NaBH.sub.4 (1.6 g) Methanol (10 mL). The
reaction mixture was stirred for 14 h, quenched with water at
5-10.degree. C., extracted with EtOAc (100 mL). The extract was
washed with brine and concentrated to give the crude product (3.5
g). It was passed through a silica gel column using EtOAc and
hexane (8:2) to give the pure product (2.5 g) as a mixture of
possible diastereoisomers. .sup.1H NMR (CDCl.sub.3, .delta.): 1.19
(s, 9H), 1.40-1.60 (m, 2H), 2.10-2.30 (m, 2H), 3.05-3.30 (m, 3H),
5.17 (m, 2H). 7.00 (m, 2H), 7.40-7.60 (m, 5H). .sup.13C NMR
(CDCl.sub.3, .delta.): 22.4, 25.6, 38.1, 45.4, 55.4, 71.1, 90.7,
111.6, 115.1, 115.4, 118.4, 122.6, 125.1, 126.5, 126.6, 131.8,
139.1, 140.1, 149.0, 160.2, 163.5.
Example 5
[0135] Synthesis of
3-[5-cyano-L-(4-flurophenyl)-1,3-dihydro-isobenzofuran-
-1-yl]-propyl amine (Didesmethylcitalopram) (3):
2-MethyL-propane-2-sulfin- ic acid
[3-[5-cyano-L-(4-flurophenyl)-1,3-dihydro-isobenzofuran-1-yl]-prop-
yl]-amide (2.0 g) was dissolved in Methanol (35 mL) at room
temperature, followed by addition of HCl (10%, 20 mL). The reaction
mixture was stirred at room temperature for 16 h. The reaction
mixture was concentrated to remove Methanol and added TBME (100
mL), water (50 mL), and aqueous potassium carbonate till basic. The
organic phase was separated and washed with water (20 mL), brine
(20 mL), and dried over sodium sulfate, concentrated to give an oil
(1.3 g) as free base. .sup.1H NMR (CDCl.sub.3, .delta.): 1.23
(broad s, 2H), 1.21.30-1.43 (m, 2H), 2.08-2.25 (m, 2H), 2.63-70 (t,
J=7 Hz, 2H), 5.10-5.20 (m, 2H). 7.00 (m, 2H), 7.38-7.60 (m,
5H).
Example 6
[0136] Synthesis of BOC-Didesmethylcitalopram (10): To a solution
of 3 (3.3 g) in dichloromethane (40 mL) was added triethylamine (10
mL) at room temperature, followed by addition of BOC anhydride (5.0
g). The reaction mixture was stirred for 1 h. The reaction mixture
was then concentrated to a residue, which was passed through a
flash silica gel column (EtOAc:Hexane 3:7) to give 3.5 product.
.sup.1H NMR (CDCl.sub.3, .delta.): 1.30-1.50 (m, 2H), 1.41 (s, 9H),
2.06-2.28 (m, 2H), 3.15 (m, 2H), 4.54 (s, 11-1), 5.10-5.21 (m, 2H),
7.00-7.06 (m, 2H), 7.30-7.42 (m, 3H), 7.50 (s, 1H), 7.60 (d, J=8
Hz, 1H). The racemic product 10 was separated by CHIRALCEL OD
column (Hexane:Ethanol 90:10) to give 10a (>99% ee, 7.20 min)
and 10b (>99% ee, 8.4 min).
Example 7
[0137] Synthesis of (+)-Didesmethylcitalopram [(+)-3]: Compound 10a
(1.3 g) was dissolved in TFA (10 mL). It was stirred at room
temperature for 1 h, and was concentrated to give a residue, which
was added water (15 mL) and EtOAc (30 mL) and aqueous potassium
carbonate till basic. Organic phase was separated and washed with
water, brine, and concentrated to give the product (0.96 g,
>95%). [(+)-3]. [.alpha.]=+5.5.degree. (C=1, Methanol). (-)-3
was prepared from 10b. Their H NMR spectra are the same as the
racemate.
Example 8
[0138] Synthesis of Didesmethylcitalopram L-tartrate (11): To a
solution of the didesmethylcitalopram free base (1.3 g) in Methanol
(20 mL) was added a solution of L-tartaric acid (0.6 g) in water (5
mL). The reaction mixture was stirred for 30 min, and concentrated
to give a white solid (1.8 g). .sup.1H NMR (DMSO-d.sub.6, .delta.):
1.26-1.60 (m, 2H), 2.24-2.30 (m, 2H), 2.70-2.80 (m, 2H), 4.03 (s,
2H), 5.10-5.25 (m, 2H), 7.15-7.20 (tm, 2H), 7.58-7.64 (m, 2H),
7.73-7.81 (m, 3H), 7.0-7.9 (broad, 4H). .sup.13C NMR (DMSO-d.sub.6,
.delta.): 23.0, 17.8, 72.7, 91.1, 111.3, 115.8, 116.0, 119.5,
123.9, 126.4, 127.6, 127.7, 132.8, 140.6, 140.9, 149.7, 160.4,
163.7, 175.4. M+ 296.9.
Example 9
[0139] Synthesis of
1-(4-fluorophenyll)-1-(3-methylamino-propyll)-1,3-dihy-
droisobenzofuran-5-carbonitrile) (Desmethylcitalopram) (2):
1-(4-fluorophenyl)-1-(3-Oxopropyl)-1,3-dihydro-isobenzofuran-5-carbonitri-
le (3.0 g) was dissolved in aqueous methylamine (10 mL, 40%). The
reaction mixture was stirred for 2 h at room temperature. It was
extracted with tert-butyl methyl ether (50 mL). The organic layer
was washed with brine and concentrated to give a crude
corresponding imine. It was dissolved in methanol (30 .mu.L), and
treated with sodium borohydride (2 g) at 10-20.degree. C. for 30
min The reaction mixture was then quenched with aqueous ammonium
chloride (50 mL) and 5 N HCl till acidic. The reaction mixture was
stirred for 10 min, followed by addition of potassium carbonate
till basic (pH>9.5). This reaction mixture was then extracted
with ethyl acetate (2.times.100 mL). The extracts were combined and
washed with water, brine and concentrated to give the crude
product. It was purified by flash chromatography
(EtOAc:MeOH:Et.sub.3N=8:1:1) to give 1.4 g titled product as free
base. .sup.1H NMR (CDCl.sub.3, .delta.): 1.30-1.66 (m, 2H),
2.10-2.30 (m, 2H), 2.35 (s, 3H), 2.53-2.60 (m, 2H), 5.10-5.25 (m,
2H), 6.94-7.05 (m, 2H), 7.40-7:62 (m, 5H). `3C NMR 8. 23.9, 35.9,
38.8, 51.4, 71.2, 90.9, 111.5, 115.0, 115.3, 118.5, 122.7, 125.1,
126.6, 126.7, 131.7, 139.4, 140.2, 149.2, 160.2, 163.5. M+310.9.
(+)-Desmethylcitalopram [(+)-2] was prepared similarly from
enantiomerically pure 8b. [.alpha.].sub.--+6.0 (c=2, Methanol).
(-)-Desmethylcitalopram [(-)-2] was prepared from enantiomer 8a.
[.alpha.]=-5.3.degree. (c=2, Methanol).
Example 10
[0140] Synthesis of Desmethylcitalopram L-tartrate (12): To a
desmethylcitalopram (1.2 g) solution in Methanol (15 mL) was added
a solution of L-tartaric acid (0.58 g) in water (2 mL). The
reaction mixture was stirred at room temperature for 1 h. The
solvent was then removed to give the final salt. .sup.1H NMR
(DMSO-d.sub.6, .delta.): 1.26-1.60 (m, 2H), 2.24-2.30 (m, 2H), 2.35
(s, 3H), 2.70-2.80 (m, 2H), 4.03 (s, 2H), 5.10-5.25 (m, 2H),
7.15-7.20 (tm, 2H), 7.58-7.64 (m, 2H), 7.73-7.81 (m, 3H), 7.0-7.9
(broad, 4H). .sup.13C NMR (DMSO-d.sub.6, .delta.): 21.4, 33.0,
37.8, 48.8, 71.9, 72.8, 91.1, 111.3, 115.8, 116.0, 119.5, 123.9,
126.4, 127.7, 132.8, 140.6, 140.8, 149.6, 159.8, 163.0, 175.5; M+
310.9
Example 11
[0141] Pharmacology: Racemic citalopram, and single enantiomers of
desmethylcitalopram and didesmethylcitalopram were compared for
their ability to inhibit the reuptake of radiolabeled serotonin
into synaptosomes prepared from various regions of rat brains. The
ability of the same compounds to inhibit the reuptake of
norepinephrine (NE) and dopamine into similarly prepared
synaptosomes was also measured to assess the selectivity of racemic
citalopram, and the (+) and (-) enantiomers of its metabolites, for
inhibition of serotonin reuptake vis-a-vis the reuptake of NE and
dopamine. The five compounds were also evaluated for their ability
to inhibit specific binding of radiolabeled ligands to the
nonselective muscarinic receptor.
[0142] IC.sub.50 values (concentration inhibiting neurotransmitter
reuptake or specific binding by 50%) were calculated by regression
analysis of the inhibition curves (Table 1).
1TABLE 1 Inhibition of Specific Muscarine Receptor Bindings and
Serotonin, Dopamine, and Norepinephrine Reuptake into Synaptosomes
by Racemic Citalopram, Enantiomeric Desmethylcitalopram and
Didesmethylcitalopram. IC.sub.50 values (in nM) for racemic
citalopram and enantiomeric metabolites on functional monoamine
uptake 5-HT uptake NE uptake DA uptake Test compounds
(-)-Didesmethylcitalopram 130 1,300 2,700 (+)-Didesmethylcitalopram
180 3,300 11,000 (-) Desmethylcitalopram 110 1,700 9,400 (+)
Desmethylcitalopram 5.8 4,100 7,600 Racemic Citalopram 2.2 4,900
13,000 Reference compounds protriptyline 0.0010/ 0.0019/ 0.0041 GBR
12909 0.0031 imipramine 0.025
[0143] Within the serotonin transporter system, values and changes
from the parent citalopram to its demethylated metabolites
correlated closely between species (Table 2)
2TABLE 2 IC.sub.50 and K.sub.i values (in nM) determined for the
racemic citalopram and enantiomeric metabolites at the human NE and
DA transporters 5-HT Transporter NE DA Rat Human Transporter
Transporter IC.sub.50 K.sub.i IC.sub.50 K.sub.i IC.sub.50 K.sub.i
IC.sub.50 K.sub.i Test Compounds (-)-Didesmethylcitalopram 27 5.5
14 5.8 5,520 5,120 38,900 17,800 (+)-Didesmethylcitalopram 19 3.9
219 90 24,200 22,400 54,700 25,000 (-)-Desmethyl 11 2.3 42 17 815
756 37,600 17,100 citalopram (+)-Desmethyl 1.3 0.27 20 8.2 10,300
9,570 27,700 12,700 citalopram Racemic 1.4 0.30 9.4 3.9 4,600 4,270
38,800 17,700 citalopram Reference Compounds Imipramine 11 4.6
Zimelidine 57 12 protriptyline 5.2/6.3 4.8 GBR12909 8.1/ 3.7
6.3/2.5
[0144] As reported previously, citalopram showed high selectivity
for the serotonin transporter in its inhibition of monoamine
neurotransmitter reuptake. The same trend continued for (+)
enantiomer of desmethylcitalopram. Contrary to prior teachings,
however, the IC.sub.50 for the (-) enantiomers or desmethyl- and
didesmethylcitalopram as well as the (+) enantiomer of
didesmethylcitalopram were within the micromolar range. On the
basis of these results, it appears that both desmethyl and
didesmethyl forms of citalopram retain significant serotonin
reuptake inhibitory activity.
* * * * *